Lyme disease is caused by infection with the tick transmitted spirochete Borrelia burgdorferi. A common manifestation of disease is arthritis, which occurs in 60% of individuals not treated at the time of the tick bite. The arthritis is characterized by edema, tendonitis, synovial hyperproliferation, and inflammatory cell infiltrate, and is associated with bacterial invasion of the affected joint. The finding that not all individuals infected with B. burgdorferi develop arthritis suggests that genetic elements of the host regulate the severity of disease. Strong support for genetic regulation of disease severity comes from studies in mice, where infected C3H/HeN mice develop severe arthritis 3-4 weeks following infection, while in BALB/c and C57BL/N mice the arthritis is mild. The histopathology of Lyme arthritis in mice is similar to that observed in humans, suggesting that common pathways regulate the severity and progression of disease in humans and mice. The genetic contribution to arthritis development is being characterized by the generation of intercross populations of mice, using the severely arthritic C3H/HeN and mildly arthritic C57BL/6N mice as parents. The F2 intercross of these strains allowed identification of four Quantitative Trait Loci that regulates arthritis severity. Two of these loci, termed Borrelia burgdorferi disease associated loci 1 and 2 (Bb1 and Bb2) were identified by measurement of swelling in rear ankles joints of infected mice. Bbl and Bb2 are located on chromosomes 4 and 5, respectively, Two other loci, Bb3 and Bb4, were identified by histopathological assessment, and map to chromosomes 5 and 11, respectively. These findings will be pursued by generation of congenic mice, in which each of the four arthritis associated Bb alleles will be introgressed onto the background of the reciprocal parent. The arthritis phenotype for each congenic mouse line will be determined by infecting with B. burgdorferi, and Bb alleles with highly penetrant phenotypes will be studied further. Recombinant congenic mice will be developed in order to narrow the physical region associated with the arthritis phenotype to 1-2 cM. The recombinant congenic mice will be used for assessment of biological functions related to arthritis development and to determine if arthritis phenotype can be transferred with hematopoietic cells. Positional cloning of arthritis regulatory genes will be initiated by developing a high resolution physical map of the 1-2 cM region associated with disease phenotype